U.S. patent number 7,141,673 [Application Number 09/868,941] was granted by the patent office on 2006-11-28 for 1-(6-methylpyridine-3-yl)-2-[4-(methylsulphonyl) phenyl] ethanone and method for its preparation.
This patent grant is currently assigned to Lonza AG. Invention is credited to Erich Armbruster, Yves Bessard, David Kuo, James E. Leresche, Ralf Proplesch, Jean-Paul Roduit.
United States Patent |
7,141,673 |
Armbruster , et al. |
November 28, 2006 |
1-(6-methylpyridine-3-yl)-2-[4-(methylsulphonyl) phenyl] ethanone
and method for its preparation
Abstract
A starting product for the preparation of COX-2 inhibitors,
notably the compound
1-(6-methylpyridine-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of
the formula (I): ##STR00001## A method for making the compound.
Inventors: |
Armbruster; Erich (Naters,
CH), Bessard; Yves (Sierre, CH), Kuo;
David (Radnor, PA), Leresche; James E. (Visp,
CH), Proplesch; Ralf (Eyholz, CH), Roduit;
Jean-Paul (Grone, CH) |
Assignee: |
Lonza AG (Basel,
CH)
|
Family
ID: |
26152856 |
Appl.
No.: |
09/868,941 |
Filed: |
January 13, 2000 |
PCT
Filed: |
January 13, 2000 |
PCT No.: |
PCT/EP00/00240 |
371(c)(1),(2),(4) Date: |
November 04, 2003 |
PCT
Pub. No.: |
WO00/42014 |
PCT
Pub. Date: |
July 20, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60145996 |
Jul 29, 1999 |
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Foreign Application Priority Data
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Jan 14, 1999 [EP] |
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99100590 |
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Current U.S.
Class: |
546/286; 546/344;
546/315 |
Current CPC
Class: |
C07D
213/57 (20130101); C07D 213/50 (20130101) |
Current International
Class: |
C07D
211/82 (20060101); C07D 211/78 (20060101) |
Field of
Search: |
;546/315,344,286 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2074674 |
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Aug 1971 |
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FR |
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WO 98/03484 |
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Jan 1998 |
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WO |
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WO 98/47871 |
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Oct 1998 |
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WO |
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WO 99/15503 |
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Apr 1999 |
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WO |
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WO 99/55830 |
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Nov 1999 |
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WO |
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Other References
Friesen et al., Bioorg. & Med. Chem. Letters, 8, (1998),
2777-2782. cited by other .
Mizzoni, (Klingsberg, Editor), Pyridineand Its Derivatives, Part
chp. IV, chp. XIV, (1964), 123-141. cited by other .
March, Advanced Organic Chemistry, 4.sup.th edition, 893-895. cited
by other.
|
Primary Examiner: McKenzie; Thomas
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Fisher, Christen and Sabol
Parent Case Text
This application is a 371 national stage application of
International Application No. PCT/EP00/00240, filed on Jan. 13,
2000, that has benefit of U.S. Provisional Application No.
60/145,996, filed on Jul. 29, 1999, and that has priority benefit
of European Patent Application No. 99100590.1, filed on Jan. 14,
1999; U.S. Provisional Application No. 60/145,996 has priority
benefit of European Patent Application No. 99100590.1.
Claims
The invention claimed is:
1. A process for preparing
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of
formula: ##STR00005## comprising initially reacting
2-methyl-5-vinylpyridine with ozone and subsequently reducing the
ozonized 2-methyl-5-vinylpyridine that is thereby converted into
2-methylpyridine-5-carbaldehyde that is used without isolation, and
reacting it with a dialkylamine and a cyano compound to give an N,N
dialkylamino-(6-methyl-3-pyridyl)-acetonitrile of formula:
##STR00006## wherein R.sup.1 and R.sup.2 are identical or different
and are C.sub.1-4-alkyl, and, finally, in the presence of a base,
reacting said acetonitrile of formula III with a
4-(methylsulfonyl)benzyl halide to give
1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of
formula I.
2. The process as claimed in claim 1, wherein the reaction of
2-methyl-5-vinylpyridine with ozone is carried out in the presence
of a mineral acid.
3. The process as claimed in claim 2, wherein the reaction of
2-methyl-5-vinylpyridine with ozone is carried out in the presence
of a mineral acid and at a temperature of from -20 to 0.degree.
C.
4. The process as claimed in claim 3, wherein the reduction is
carried out using an alkali metal hydrogen sulfite, with formation
of 1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt of
formula II: ##STR00007## wherein M is an alkali metal.
5. The process as claimed in claim 4, wherein the reduction is
carried out at a temperature of from -20 to 20.degree. C.
6. The process as claimed in claim 5, wherein the
1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt is used
without isolation for preparing the
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile of formula
III.
7. The process as claimed in claim 6, wherein the cyano compound
used in the reaction of the 2-methylpyridine-5-carbaldehyde is an
aqueous HCN solution or an aqueous solution of an alkali metal
cyanide.
8. The process as claimed in claim 7, wherein the temperature for
the reaction of the 2-methylpyridine-5-carbaldehyde with the
dialkylamine and the cyano compound is from 0 to 30.degree. C.
9. The process as claimed in claim 8, wherein the base used in the
reaction of the N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile
of formula III is either an aqueous alkali metal hydroxide solution
together with a phase-transfer catalyst or an alkali metal alkoxide
in the presence of an organic solvent.
10. The process as claimed in claim 9, wherein the
2-methyl-5-vinylpyridine is obtained using 2-methyl-5-ethylpyridine
as starting material.
11. The process as claimed in claim 10, wherein
2-methyl-5-ethylpyridine is converted at from 500 to 700.degree. C.
in the presence of a catalyst into 2-methyl-5-vinylpyridine.
12. The process as claimed in claim 11, where the catalyst used is
a member selected from the group consisting of a silica, silica
gel, iron oxide, zinc oxide, chromium oxide, copper chromite,
magnesium oxide, potassium oxide, aluminum oxide, borophosphate,
and mixtures thereof, and is on a support or is unsupported.
13. The process as claimed in claim 12, wherein the reaction is
carried out at a temperature of from 600 to 700.degree. C.
14. The process as claimed in claim 1, wherein the reduction is
carried out using an alkali metal hydrogen sulfite, with formation
of 1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt of
formula II: ##STR00008## wherein M is an alkali metal.
15. The process as claimed in claim 14, wherein the reduction is
carried out at a temperature of from -20 to 20.degree. C.
16. The process as claimed in claim 15, wherein the
1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt is used
without isolation for preparing the
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile of formula
III.
17. The process as claimed in claim 1, wherein the cyano compound
used in the reaction of the 2-methylpyridine-5-carbaldehyde is an
aqueous HCN solution or an aqueous solution of an alkali metal
cyanide.
18. The process as claimed in claim 17, wherein the temperature for
the reaction of the 2-methylpyridine-5-carbaldehyde with the
dialkylamine and the cyano compound is from 0 to 30.degree. C.
19. The process as claimed in claim 18, wherein the base used in
the reaction of the
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile of formula III
is either an aqueous alkali metal hydroxide solution together with
a phase-transfer catalyst or an alkali metal alkoxide in the
presence of an organic solvent.
20. The process as claimed in claim 9, wherein the
2-methyl-5-vinylpyridine is obtained using 2-methyl-5-ethylpyridine
as starting material.
21. The process as claimed in claim 20, wherein
2-methyl-5-ethylpyridine is converted at from 500 to 700.degree. C.
in the presence of a catalyst into 2-methyl-5-vinylpyridine.
22. The process as claimed in claim 21, wherein the catalyst used
is a member selected from the group consisting of a silica, silica
gel, iron oxide, zinc oxide, chromium oxide, copper chromite,
magnesium oxide, potassium oxide, aluminum oxide, borophosphate,
and mixtures thereof, and is on a support or is unsupported.
23. The process as claimed in claim 22, wherein the reaction is
carried out at a temperature of from 600 to 700.degree. C.
24. A 1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt of
formula: ##STR00009## wherein M is an alkali metal.
25. A process for preparing a
1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt as
claimed in claim 24, comprising reacting 2-methyl-5-vinylpyridine
with ozone subsequently reducing the ozonized
2-methyl-5-vinylpyridine with an alkali metal hydrogen sulfite to
convert the reduced, ozonized 2-methyl-5-vinylpyridine into the end
product of formula II.
26. An N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile of
formula: ##STR00010## wherein R.sup.1 and R.sup.2 are identical or
different and are C.sub.1-4-alkyl.
27. A process for preparing a
N,N-dialkylamino-(6-methyl-3-Pyridyl)-acetonitrile of formula III
as claimed in claim 26, wherein 2-methylpyridine-5-carbaldehyde or
1-hydroxy-(6-methylpyridin-3-yl)-methanesulfonic acid salt of
formula II: ##STR00011## is reacted with a dialkylamine and a cyano
compound to give the end product of formula III.
28. A process for preparing
1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of
formula: ##STR00012## comprising: in a first step (a), converting
2-methyl-5-ethylpyridine at from 500 to 700.degree. C. in the
presence of a catalyst into 2-methyl-5-vinylpyridine, in a second
step (b), reacting the 2-methyl-5-vinylpyridine with ozone and,
subsequently, reducing the ozonized 2-methyl-5-vinylpyridine to
convert it into 2-methylpyridine-5-carbaldehyde, in a third step
(c), converting 2-methylpyridine-5-carbaldehyde using a
dialkylamine and a cyano compound into the corresponding
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile, and finally, in
a last step (d), the
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile is reacted in
the presence of a base with a 4-(methylsulfonyl)benzyl halide to
give 1-(6-methylpyridin-3-yl)-2-[4-methylsulfonyl)phenyl]ethanone.
Description
The invention comprises a novel process for preparing
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl) phenyl]ethanone of
the formula
##STR00002##
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone is
an important intermediate for preparing so-called COX-2 inhibitors,
pharmaceutically active compounds having analgesic and
anti-inflammatory action (R. S. Friesen et al., Bioorganic &
Medicinal Chemistry Letters 8 (1998) 2777 2782; WO 98/03484).
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone of
the formula I is a novel compound which is not known from the
literature. It was the object of the invention to provide a novel
intermediate for the production of COX-2-inhibitors and to provide
an industrially feasible process for preparing the novel
intermediate of the formula I. The object was achieved by the novel
process and compound according to patent claims 1 and 2.
The process according to the invention is characterized by four
steps, where in the first step a) 2-methyl-5-ethylpyridine is
converted at from 500.degree. C. to 700.degree. C. in the presence
of a catalyst into 2-methyl-5-vinylpyridine,
in the second step b) the 2-methyl-5-vinylpyridine is converted
with ozone and subsequent reductive work-up into
2-methylpyridine-5-carbaldehyde,
in the third step c) the 2-methylpyridine-5-carbaldehyde is
converted with a dialkylamine and a CN compound into the
corresponding N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile
and finally in the last step d) the
N,N,-dialkylamino-(6-methyl-3-pyridyl)acetonitrile is reacted in
the presence of a base with a 4-(methylsulphonyl)benzyl halide to
give
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone to
give the end product.
A considerable advantage of the process according to the invention
consists in the fact that industrially available
2-methyl-5-ethylpyridine can be used as starting material.
Step a:
The dehydration of 2-methyl-5-ethylpyridine to give
2-methyl-5-vinylpyridine is known from the literature (for example
A. Nenz et al., Hydrocarbon Processing, 47(11), 1968, 139 144; U.S.
Pat. No. 2,769,773).
The reaction proceeds at from 500.degree. C. to 700.degree. C. in
the presence of a large number of different catalysts. In general,
catalysts based on silica, silica gel, iron oxide, zinc oxide,
chromium oxide, copper chromite, magnesium oxide, potassium oxide,
alumina or boron phosphate, alone or as a mixture, if appropriate
applied to a support, are employed. Good results can be obtained
inter alia with a zinc oxide catalyst applied to pumice as support.
It is furthermore advantageous for the reaction to dilute the
2-methylpyridine with steam or an inert gas, but preferably with
steam.
The 2-methyl-5-vinylpyridine can be purified in a simple manner,
for example by removal of the aqueous phase and subsequent steam
distillation or vakuum distillation, such that it is suitable for
the subsequent step b).
Step b:
The reaction with ozone is advantageously carried out in the
presence of a mineral acid at a temperature of from -20.degree. C.
to 0.degree. C., preferably at a temperature of from -15.degree. C.
to -5.degree. C. Suitable mineral acids are sulphuric acid or
phosphoric acid, and in particular sulphuric acid. Suitable
reaction media are water and/or a polar solvent. As a polar solvent
C.sub.1-6 alcohols can be used such as methanol, ethanol, propanol,
butanol, pentanol or hexanol. Mixtures of a lower alcohol, such as
methanol or ethanol, with water have been found to be useful.
The ozone complex which is formed as an intermediate is worked up
reductively, preferably with an alkali metal hydrogen sulphite, to
obtain the 2-methyl-5-carbaldehyde.
Suitable alkali metal hydrogen sulphites are sodium or potassium
hydrogen sulphite. However, it is also possible to choose other
known reducing agents, such as, for example, dimethyl sulphide,
thiourea or trimethyl phosphite, or hydrogen in the presence of a
suitable catalyst.
In the case of the preferred reductive work-up with alkali metal
hydrogen sulphite, the reaction is carried out in essentially the
same medium as used for the ozonization, generally at a temperature
of from -20.degree. C. to 20.degree. C., preferably from
-10.degree. C. to 0.degree. C.
Depending on the further work-up steps, the
2-methylpyridine-5-carbaldehyde or an adduct of alkali metal
hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde can be
formed, namely a 1-hydroxy-(6-methylpyridine-3-yl)methansulfonic
acid salt.
If it is desired to isolate the 2-methyl-5-carbaldehyde, it is
possible to selectively extract the reaction mixture at a pH of
about 4 to 5 with a suitable organic solvent, such as, for example,
with ethyl acetate. Alternatively, but preferred, an adduct of
alkali metal hydrogen sulphite with the
2-methylpyridine-5-carbaldehyde may be formed initially, which is
then cleaved at a pH of about 10 into the
2-methyl-5-carbaldehyde.
Particularly preferably, however, the adduct of alkali metal
hydrogen sulphite with the 2-methylpyridine-5-carbaldehyde is
employed immediately for further reaction in step c). Thus, it is
possible to circumvent isolation of the relatively unstable
2-methylpyridine-5-carbaldehyde in an elegant manner.
The adduct of alkali metal hydrogen sulphite with the
2-methylpyridine-5-carbaldehyde is novel and not known from the
literature and accordingly also part of the subject-matter of the
invention. The adducts have the general formula
##STR00003## in which M is an alkali metal, and are referred to as
1-hydroxy-(6-methylpyridin-3-yl)methanesulphonic acid salts. The
alkali metal M is advantageously Na or K. Step c:
The reaction of the 2-methylpyridine-5-carbaldehyde or the adduct
of alkali metal hydrogen sulphite with the
2-methylpyridine-5-carbaldehyde is carried out according to the
principle of the Strecker synthesis using a CN compound and a
dialkylamine to give the corresponding
N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile.
An aqueous HCN solution or an aqueous solution of an alkali metal
cyanide may serve as CN compound here. Particulary suitable
dialkylamines are C.sub.1-4-dialkylamines, wherein C.sub.1-4 alkyl
means methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tertiary-butyl. More preferd dialkylamines are dimethylamine or
diethylamine.
The reaction temperature is advantageously in the range of from
0.degree. C. to 30.degree. C.
It may be advantageous to add a water-immiscible solvent, such as,
for example, toluene or t-butyl methyl ether. Work-up and isolation
of the corresponding
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitrile can then be
carried out by simple phase separation. The
N,N-dialkylamino-(6-methyl-3-pyridyl)-acetonitriles of the general
formula
##STR00004## wherein R1 and R2 are identical or different and are
C.sub.1-4-alkyl, are novel compounds which are not known from the
literature, and in consequence form part of the subject-matter of
the invention as does the process for their manufacture.
As said above, C.sub.1-4-alkyl specifically means methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The preferred
meaning of Alkyl is methyl or ethyl.
Step d:
The conversion of the
N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile by reaction with
the 4-(methylsulphonyl)benzyl halide to give the end product of the
formula I is carried out in the presence of a base. A suitable
4-(methylsulphonyl)benzyl halide is 4-(methylsulphonyl)benzyl
chloride.
The base used can be an aqueous alkali metal hydroxide solution,
preferably an aqueous sodium hydroxide solution, where in this case
the presence of a customary phase-transfer catalyst is useful.
Suitable phase-transfer catalysts are, for example,
tetraalkylammonium halides, such as, for example,
tetra-n-butylammonium chloride or tetra-n-butylammonium bromide.
The reaction temperature is in the range of from 40.degree. C. to
70.degree. C. It may be advantageous to add a water-immiscible
solvent, such as, for example, toluene, methylene chloride or
t-butyl methyl ether.
Alternatively and preferably, the base used is an alkali metal
alkoxide. Suitable alkali metal alkoxides are, for example, sodium
tert-butoxide, potassium tert-butoxide or sodium tert-pentoxide,
and preferably potassium tert-butoxide. Recommended solvents are
ethers, such as, for example, tetrahydrofuran. The reaction
temperature in this variant is generally from 15.degree. C. to
25.degree. C.
The
1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone
can be isolated in a manner known to the person skilled in the art,
for example by acidifying the reaction mixture, followed by
extraction with, for example, toluene. Further purification can be
carried out by recrystallization, for example in acetonitrile.
EXAMPLE 1
Preparation of 2-methyl-5-vinylpyridine
Pumice having a particle size of from 6 to 8 mm is moistened with
water and mixed with 25% of its dry weight of zinc oxide in powder
form, filled moist into the reactor (length of the tube 750 mm,
diameter of the tube 60 mm) and left in a stream of nitrogen at
from 650.degree. C. to 700.degree. C. for 24 h.
76 ml/h of 2-methyl-5-ethylpyridine together with 87 ml/h of steam
were passed over the abovementioned catalyst at from 670.degree. C.
to 680.degree. C. and 665 mbar. At the end of the reactor, a
product stream consisting of 40.6% by weight of
2-methyl-5-vinylpyridine and 56.3% of 2-methyl-5-ethylpyridine was
taken off. Based on reacted 2-methyl-5-ethylpyridine, a yield of
93.0% was achieved. To prepare pure 2-methyl-5-vinylpyridine, the
product mixture was subsequently subjected to steam distillation
(266 mbar, overhead temperature 59.degree. C. 60.degree. C.) or to
vakuum distillation (20 mbar, temperature 90.degree. C.).
EXAMPLE 2
Preparation of 2-methylpyridine-5-carbaldehyde
11.92 g of 2-methyl-5-vinylpyridine (content 85%, 85 mmol), 50 ml
of methanol and 10 ml of water were initially charged. Concentrated
sulphuric acid (9.81 g, 98 mmol) was metered in such that the
temperature did not exceed 20.degree. C. The solution was cooled
from -12.degree. C. and an ozone/oxygen mixture (about 5% O.sub.3
in O.sub.2, 50 l/h) was introduced until the
2-methyl-5-vinylpyridine had reacted completely. Water (50 ml) and
40% aqueous NaHSO.sub.3 solution (22.7 g, 85 mmol) were carefully
metered in. The reaction mixture was warmed to 20.degree. C. and
neutralized using 30% NaOH (about 32 g, 0.24 mol). Methanol was
distilled off at 30 40.degree. C., and then, to form the bisulphite
adduct, another 22.7 g of 40% NaHSO.sub.3 solution were added. The
mixture was stirred for 30 min, after which the pH was readjusted
to neutral, and the neutral impurities were subsequently extracted
using 35 ml of t-butyl methyl ether. The aqueous phase was adjusted
to pH 10 using 30% NaOH, and 26.5 g of Na.sub.2CO.sub.3 (0.25 mol)
were added. The liberated aldehyde was extracted using 2.times.80
ml of t-butyl methyl ether. Concentration of the solvent gave 9 g
of 2-methylpyridine-5-carbaldehyde as a slightly yellowish oil.
TABLE-US-00001 .sup.1H-NMR(CDCl.sub.3): 2.66(s, 3H); 7.35(d, J=8Hz,
1H); 8.07(dd, J=8Hz and 2.1Hz, 1H); 8.96(d, J=2.1Hz, 1H); 10.08(s,
1H). .sup.13C-NMR(CDCl.sub.3): 24.98(CH3); 123.72(C-5);
129.32(C-3); 135.88(C-4); 151.87(C-2); 164.87(C-6);
190.51(C=0).
EXAMPLE 3a
Preparation of N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile
(from 2-methylpyridine-5-carbaldehyde)
At from 10.degree. C. to 15.degree. C., 73.2 g (1.25 eq.) of
diethylamine and 100.3 g (1.15 eq.) of a 25% HCN solution were
added simultaneously over a period of one hour to a mixture of 98.3
g (1.0 eq.) of 2-methylpyridine-5-carbaldehyde in 200 ml of water
and 200 ml of toluene which was stirred efficiently. The reaction
mixture was stirred at 30.degree. C. for 3 h.
The phases were then separated and the aqueous phase was extracted
with 2.times.100 ml of toluene. The organic phases were combined
and the toluene was then removed, giving the title product in the
form of a yellowish oil and in a yield of 172.3 g (90.1%).
TABLE-US-00002 .sup.1H-NMR(CDCl.sub.3): 8.65(1H, s); 7.75(1H, d);
7.20(1H, d); 5.00(1H, s); 2.68(2H, m); 2.59(13H, s); 2.50(2H, m);
1.10(6H, t). .sup.1H-NMR(D.sub.6-DMSO): 8.50(1H, s); 7.70(1H, d);
7.32(1H, d); 5.45(1H, s); 2.58(2H, m); 2.50(3H, s); 2.40(2H, m);
1.02(6H, t).
EXAMPLE 3b
Preparation of N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile
(via the adduct of 2-methylpyridine-5-carbaldehyde with sodium
hydrogen sulphite)
The ozonolysis was carried out as in Example 2, starting from 23.84
g of 2-methyl-5-vinylpyridine (83.1% GC, 166.2 mmol). After the
impurities had been extracted at neutral pH, the aqueous phase was
cooled to 15.degree. C. and diethylamine (21.94 g, 0.3 mol) and
then 9.8 g of NaCN (0.2 mol) were added (in each case addition over
a period of 10 min). The solution was stirred at 15.degree. C. for
4.5 h, and the product was subsequently extracted with 3.times.85
ml of toluene. The combined extracts were concentrated. Obtained:
37.4 g of N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile as an
orange oil. Content: 83.7% (GC, % by weight), 0.34% of aldehyde).
Yield: 92.7% based on 2-methyl-5-vinylpyridine.
TABLE-US-00003 .sup.1H-NMR(CDCl.sub.3): 1.08(t, 6H); 2.50(m, 2H);
2.58(s, 3H); 2.65(m, 2H); 5.00(s, 1H); 7.18(d, J=8Hz, 1H); 7.74(dd,
J=8Hz, 2Hz, 1H); 8.66(d, J=2Hz, 1H).
EXAMPLE 3c
Preparation and characterization of the adduct of
2-methylpyridine-5-carbaldehyde with sodium hydrogen sulphite
After the addition of bisulphite, the .sup.1H-- and .sup.13C-NMR of
a sample were measured. The NMR signals of the aldehyde had
disappeared completely, and the following signals were observed
instead:
TABLE-US-00004 .sup.1H-NMR(DMSO-d.sub.6): 1.96(s, 3H); 5.01(s, 1H);
6.85(d, J=8Hz, 1H); 7.45(dd, J=8 and 2Hz, 1H); 7.93(d, J=2Hz, 1H).
.sup.13C-NMR(DMSO-d.sub.6): 20.23(CH3); 81.78(CH); 124.14(C-5);
130.02(C-3); 138.76(C-4); 143.08(C-2); 156.04(C-6).
EXAMPLE 4a
Preparation of
1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone
(aqueous NaOH as base)
41.07 g (89.1%, 1.00 eq.) of
N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile, 30 ml of
toluene and 10.0 g of Celite were initially charged. 72 g (5 eq.)
of a 50% aqueous NaOH solution were then added over a period of 15
minutes such that the temperature could be maintained at 20.degree.
C. The reaction mixture was heated to 45.degree. C. With vigorous
stirring, a first portion of 0.32 g of tetra-n-butylammonium
bromide was added. Immediately after that, a solution of 0.32 g of
tetra-n-butylammonium bromide and 44.52 g (1.2 eq.) of
4-(methylsulphonyl)benzyl chloride in 200 ml of toluene was added
over a period of 1.5 h. After half had been added, a third portion
of 0.32 g of tetra-n-butylammonium bromide was added, and stirring
was continued at 45.degree. C. for 6 h.
The reaction mixture was then warmed to room temperature, and 100
ml of water and 100 ml of toluene were then added. The mixture was
filtered, the residue was washed with 25 ml of toluene and the
phases were then separated. The aqueous phase was extracted with
2.times.50 ml of toluene. The combined organic phases were then
extracted with 380 ml of 1N HCl. Neutralization with 29.6 g of 50%
aqueous NaOH solution to pH 4.5 resulted in the title product
crystallizing out. The suspension was filtered and the product was
washed with 2.times.100 ml of water and 2.times.80 ml of
isopropanol/water 1:1 and subsequently dried at 20.degree. C./20
mbar. This gave 40.19 g (76.4%) of the title product having a
content of 99.0%. M.p. 182.degree. C. 183.degree. C.
TABLE-US-00005 .sup.1H-NMR(CDCl.sub.3): 9.15(1H, s); 8.18(1H, d);
7.92(2H, d); 7.47(2H, d); 7.30(1H, d); 4.39(2H, s); 3.04(3H, s);
2.63(3H, s).
EXAMPLE 4b
Preparation of
1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone
(alkoxide, anhydrous)
At 20.degree. C., 48.16 g (84.5%, 1.00 eq.) of
N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile in 20 ml of
tetrahydrofuran were added over a period of 30 minutes to a
suspension of 38.58 g (1.7 eq.) of potassium t-butoxide in 60 ml of
tetrahydrofuran. Immediately afterwards, 42.59 g (1.03 eq.) of
4-(methylsulphonyl)benzyl chloride in 60 ml of tetrahydrofuran were
added at from 20.degree. C. to 25.degree. C. over a period of 1.5
h.
The reaction mixture was stirred at 20.degree. C. for 0.5 h and
then diluted with 100 ml of water, and adjusted to pH 2 by addition
of 180 ml of 2N HCl over a period of one hour. After a further 0.5
h at 20.degree. C., the mixture was adjusted to pH 3 using 10 g of
a 30% aqueous NaOH solution. The suspension was stirred at
20.degree. C. for one hour and then filtered, and the product was
washed with 2.times.150 ml of water and 2.times.100 ml of
water/isopropanol 1:1. Drying at 20.degree. C./20 mbar gave 53.72 g
(92%) of the title product having a content of 99.1%. M.p.
182.degree. C. 183.degree. C.
TABLE-US-00006 .sup.1H-NMR(CDCl.sub.3): 9.15(1H, s); 8.18(1H, d);
7.92(2H, d); 7.47(2H, d); 7.30(1H, d); 4.39(2H, s); 3.04(3H, s);
2.63(3H, s).
* * * * *